History of Endodontics aae/abe

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Periapical Pathogenesis

Marton JOE 2014 – Review of Immunological mechanisms in development of AP

  1. Initial Inflammatory Response – Innate immune mechanisms (0-48 hrs)

    1. Human PDL fibroblasts (PDLFs) – TLR response to Bacterial PAMPs (LPS, Peptidoglycan)

      1. Upregulation of pro-inflammatory cytokines: TNF-, IL-6, PMN chemoattractant

      2. Upregulation of anti-inflammatory cytokines: TGF-

    2. EBV, CMV, Herpes virus (Sabeti) contribute to stimulation of pro-inflammatory mediators – cytokines/chemokines

    3. Vasodilation/Inc. vascular permeability, leukocyte chemotaxis/activation (PMNs, Macrophages), Phagocytosis (DCs, Macrophages), Cytokine/Chemokine production

  2. Adaptive immune mechanisms (>48 hrs)

    1. APCs initiate differentiation of T cells, activation of macrophages/NKCs, specific antibody production

Periapical Pathogenesis

Marton JOE 2014 – Review of Immunological mechanisms in development of AP

  1. Dynamics of Periapical Bone destruction and repair

    1. Early AP: TH1 cells predominant (Stashenko) in early AP development and expansion. VEGF and angiogenesis associated with lesion expansion.

    2. Late AP: TS cells, plasma cells/B cells/TH2 cells in late AP – lesion stabilization and healing (post 21 days – Stashenko)

    3. MMPs: destruction of ECM by MMPs initiates bone resorption

    4. Equilibrium of RANK-L and Osteoprotegrin (OPG)

      1. RANKL expressed by osteoblasts, monocytes, DCs, fibroblasts, endothelial cells, PMNs, and activated T lymphocytes

      2. TNF-, IL-1, IL-6, IL-17, Bradykinin, PGE2  RANKL/Osteoclast expression

      3. IFN-, IL-10, TGF-  RANKL/Osteoclast expression

    5. Bone loss self limiting - Equilibrium develops between destructive and repair mechanisms PDL derived stem cells adjacent to PA lesion may engineer bone, PDL, and cementum repair thru stimulation by growth factors such as TGF-

Cytokines and their activity

Cytokines are soluble polypeptide products of immune cells.

  1. Modify behavior of other cells

  2. Produce systemic effects

  3. Act as growth factors

  1. Stashenko IL-1β, TNF-α, PGE2, Bradykinin, and LPS – stimulate resorption either alone or in synergistic combination

  2. Safavi – TNF-α identified in periapical exudates from CAP

  3. Stashenko – IL-1α, IL-1β, TNF-α and lymphocyte-derived lymphotoxin potentially stimulate resorption and inhibit reparative bone formation

What cells are found in a periapical granuloma?

Stern – (FMLP = Fibroblasts Macrophages Lymphocytes Plasma Cells PMNs)

Inflammatory Cells = 52% of all cells

  1. Macrophage = 24%

  2. Lymphocyte = 16%

  3. Plasma cells = 7%

  4. PMNs = 4%

Other Cells

  1. Fibroblasts = 42%

  2. Epithelial Cells = 5%

  3. Vascular cells = 6%

StashenkoT lymphocytes 50%, PMNs 35%, Plasma cells, Macrophages 15%

Perrini – found mast cells in varying stages of activity

Pulver – found 70% IgG, 14% IgA, 10% IgE and 4% IgM (GAEM)

Cysts have 45% IgG, 45% IgA, 5% IgE and 5% IgM (higher IgA)

Torabinejad – Granulomas & Cysts have T and B cells, T Cells were in greater quantity.

Who studied LPS?


  1. Pulpless teeth contain greater concentration than vital teeth

  2. Symptomatic w/ AP contained greater concentrations than asymptomatic


  1. Endotoxin activity correlated with the presence and number of Gram – bacteria

Horiba –

  1. Higher concentrations in symptomatic teeth than asymptomatic

  2. Higher concentrations in teeth with radiolucencies

  3. Higher concentrations in teeth with exudation than without

Zones of Fish (NCIS)

Describes body’s way of isolating and localizing an infection in periradicular area

  1. Infection/ Necrosis – Bacteria, PMNs (Innate Acute 0-48 hrs)

  2. Contamination – Bacterial toxins, macrophages, lymphocytes (Innate Chronic 48hrs +)

  3. Irritation – Macrophages, osteoclasts, lymphocytes, plasma cells (Adaptive)

  4. Stimulation – Osteoblasts, fibroblasts (Proliferative phase)

Symptomatic Apical Periodontitis

What is SAP?

Immediate Innate Immune response to diffusion of inflammatory mediators, bacteria and bacterial toxins/enzymes/byproducts (TEBs) into the periapical tissues

Cells Involved

  1. Mast Cells – Histamine, Leukotrienes, Cytokines, PGs released

  2. Endothelial Cells – Vasodilation/Inc Vascular Permeability

  3. PMNs – Principal cell of Acute immune response – peak 24-48 hrs – recrutied/activated by PAMPs, cytokines, chemokines  phagocytosis, release of inflammatory mediators, recruitment of leukocytes

  4. Macrophages – 2nd wave in acute immune response – peak 48-96 hrs – activated by PAMPs, cytokines, chemokines – phagocytosis, release of inflammtory mediators, recruitment of leukocytes

Inflammatory mediators

Histamine, PGs, Cytokines/Chemokines, Complement, Bradykinin, Neuropeptides

Outcomes Abscess formation or Progression to Chronic apical inflammation

Acute Apical Abscess

What is AAA?

Inflammatory reaction to direct bacterial invasion of inflammed periapical tissues by specific pyogenic bacteria characterized by a focal collection of purulent exudate surrounded by granulomatous layer

Cells Involved

  1. PMNs – Predominant cell in AAA – secretion of lysozymal enzymes and free oxygen radicals during phagocytosis of bacteria leads to connective tissue (ECM) destruction

  2. Live/Dead Bacterial cellsPyogenic bacteria resistant to phagocytosis

Composition of Purulent exudate

Dead/Live PMNs, Dead/Live bacteria/byproducts, Disintegrated ECM/CT, Lysozymal enzymes

Inflammatory mediators

Similar to SAP

Asymptomatic Apical Periodontitis

What is AAP?

Adaptive immune response characterized by persistence of inflammatory stimuli, adaptation of host immune response, destruction of periapical tissues with formation of a granulomatous lesion and initiation of repair process

Cells Involved

  1. Macrophages – APCs, Activated for bacterial phagocytosis,  cytokines

  2. Lymphocytes – T lymphocytes – activation of Macrophages/NKCs, B cell differentiation; B lymphocytes – APCs, Antibody production

  3. Dendritic Cells - APCs

  4. Osteoclasts – Bone destruction – RANKL: IL-1, IL-6, TNF, PGs, BK

  5. Fibroblasts – Chronic inflammation/wound healing – Collagen prod.

Inflammatory Mediators

Similar to SAP with different composition of adaptive cytokines present

Key features

Proliferation of Fibrovascular Granulomatous lesion, Bone destruction, External apical root resorption (cementum/dentin) – see Filippe, Vier

Radicular Cyst

What is a radicular cyst?

Pathologic cavity completely lined by non-keratinized stratitifed squamous epithelium of variable thickness and contained within a granulomatous AP lesion

Types of cysts

Pocket or Bay cyst – Attached to the AF of root, lumen opens to canal

True cystNO attachment to the root structure, completely enclosed by lining epithleium

Cells Involved

Same a AAP with Epithelial Cells most prominent cell type

Inflammatory Mediators

Similar to AAP

Key Features

Asymptomatic Cyst formation within Fibrovascular granulomatous lesion

Extraradicular Infections

What is an extraradicular infection?

Bacterial infection established outside the confines of the root canal space within the periapical tissues

Types of E.I.

  1. Continuous with an intraradicular infection

  2. Independent of an intraradicular infection


  1. Biofilm

  2. Planktonic


Rare: Usually associated with actinomycosis/proprionib. (Nair, Siqueira, Sjogren)

Ricucci/Siquiera – 6% Extraradicular bioflim presence in AP cases, typically planktonic bacteria associated with abscess

More common: See Tronstad/Barnett, Sunde/Tronstad (35/36 AAP/CAA Sx)

NOTE: Testing can only be done through surgical biopsy or microbiologic sampling during apical surgery which may be subject to contamination

Periapical Pathology - Diagnosis
Granuloma = Localized mass of chronic inflammatory tissue consisting of macrophages, T lymphocytes, and a variable number of plasma cells, PMNs, mast cells, giant cells and epithelium formed in reaction to infection of the dental pulp which serves as a constant source of antigenic material
Abscess = Focal collection of purulent exudate composed of dead and live PMNs, disintegrated cells, degraded ECM, lysozymal enzymes, dead and live bacteria and toxins surrounded by a layer of viable PMNs and granulomatous tissue
Cyst = Pathologic cavity completely lined by non-keratinized stratiifed squamous epithelium of variable thickness and contained within a granulomatous AP lesion

Periapical Pathology - Diagnosis

  1. Simon – Granuloma 54.3%, Abscess 5.7%, Epithelialized Granuloma 22.9%, True Cyst 8.6%, Bay Cyst 8.6%

  1. Nair – Incidence of Cyst, Abscess, and Granuloma:

Granuloma 50%, Abscess 35%, Cyst 15%, (True 9%, Pocket 6%) – need for

Serial biopsy to establish cyst vs. epithlialized granuloma

  1. Spattafore 1990– 1659 (~1700) apical biopsies: Granulomas 52%, Cyst 42%, Apical Scar 2%, Other 4% (rule of 2’s)

  1. Koivisto 2012 – 9723 (~9700) jaw lesions (excludes: angle/ramus mandible): Granulomas 40%, Cysts 33%, Others 20%: KCOT 8%, CGCG 1%, Ameloblastoma 1%, Metastatic Carcinomas <1%

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